1. Field of the Invention
This invention relates to novel, aromatic compounds and pharmaceutically-acceptable salts thereof which possess useful pharmacological properties. More particularly the compounds of the invention are antagonists of the pain enhancing effects of E-type prostaglandins. The invention also relates to processes for the manufacture of the aromatic compounds and pharmaceutically-acceptable salts thereof; to novel pharmaceutical compositions containing them; and to use of the compounds in pain relief.
2. Description of the Related Art
The compounds of the invention are useful in the treatment of pain such as the pain associated with joint conditions (such as rheumatoid arthritis and osteoarthritis), post-operative pain, postpartum pain, the pain associated with dental conditions (such as dental caries and gingivitis), the pain associated with bums (including sunburn), the treatment of bone disorders (such as osteoporosis, hypercalcaemia of malignancy and Paget""s disease), the pain associated with sports injuries and sprains and all other painful conditions in which E-type prostaglandins wholly, or in part, play a pathophysiological role.
Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates are the main classes of drugs in pain relief. However both possess undesirable side effects. NSAIDS are know to cause gastrointestinal irritation and opiates are known to be addictive.
Aromatic compounds which antagonize the pain-enhancing effects of E-type prostaglandins are disclosed in U.S. Pat. Nos. 5,811,459; 5,834,458 and 5,843,942. However, the need for compounds which relieve pain, without side effects, continues to exist.
We have now found a class of compounds structurally different than NSAIDS and opiates, and useful in the relief of pain.
The compounds of the invention may also possess antiinflammatory, anti-pyretic and anti-diarrheal properties and be effective in other conditions in which prostaglandin E2 (PGE2) wholly or in part plays a pathophysiological role. 
According to the invention there is provided a compound the formula I;
wherein:
A is an optionally substituted: phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyramidal, thienyl, thiazolyl, oxazolyl or thiadiazolyl;
B is an optionally substituted: phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl, isoxazole, pyrazole, furyl, pyrrolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridone, pyrimidone, pyrazinone or pyridazinone;
X is optionally substituted: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or phenyl.
R1 is CO2H, CO2R, COSO2NR2, tetrazolyl, P(O) or (OR)2 or SONH2 
R2 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or C1-3 alkylaryl
R3 is H or C1-5 alkyl
R4 is H or C1-5 alkyl
Any of the above alkyl, alkenyl, alkynyl or aryl groups may optionally be substituted.
Particular substituents for ring carbon atoms in A and X include halo, trifluoromethyl, nitro, hydroxy, amino, C1-4alkylamino, diC1-4alkylamino, cyano, C1-6alkoxy, xe2x80x94S(O)pC1-6 alkyl (wherein p is 0, 1 or 2), C1-6alkyl (optionally substituted by hydroxy, amino, halo, nitro or cyano), xe2x80x94S(O)p CF3 (wherein p is 0, 1 or 2), carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C2-6alkenyl, C2-6alkynyl, C2-4alkenylamino, Nxe2x80x94C2-4alkenyl-Nxe2x80x94C1-4alkylamino, di-C2-4alkenylamino, S(O)p C2-6alkenyl (wherein p is 0, 1 or 2), C2-4alkenylcarbamoyl, N-C2-4alkenyl-N-alkylamino, di-C2-4alkenylcarbamoyl, C3-7cycloalkyl, C3-7cycloalkylC1-3 alkyl, C3-7cycloalkylC2-3alkenyl, C5-7cycloalkenyl, C5-7cycloalkenylC1-3alkyl, C5-7cycloalkenylC2-3alkenyl, C5-7cycloalkenyl C2-3alkynyl, C1-4alkoxycarbonylamino, C1-4alkanoylamino, C1-4alkanoyl(Nxe2x80x94C3-4alkyl)amino, C1-4alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C1-4alkylaminosulphonyl, di(C1-4alkyl)aminosulphonyl, C1-4alkoxycarbonyl, C1-4alkanoyloxy, C1-6alkanoyl, formylC1-4alkyl, trifluoroC1-3alkylsulphonyl, hydroxyimino C1-6 alkyl, C1-4alkoxyiminoC1-6alkyl C1-6alkylcarbamoylamino, oxazoly, pyridyl, thiazolyl, pyrimidyl, pyrazinyl and pyridazinyl.
Where a ring nitrogen atom in A can be substituted without becoming quaternised, it is unsubstituted or substituted by C1-4alkyl.
Particular substituents for ring carbon atoms in B include halo, amine, C1-4alkylamino, di(C1-4alkyl)amino, trifluoromethyl, nitro, hydroxy, C1-6alkoxy, C1-6 alkyl, cyano, xe2x80x94S(O)pC1-6 alkyl (wherein p is 0, 1 or 2), carbamoyl, C1-4alkylcarbamoyl and di(C1-4alkyl)carbamoyl.
Where a ring nitrogen atom in B can be substituted without becoming quaternised, it is unsubstituted or substituted by C1-4 alkyl.
Preferably A is phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl or thiadiazolyl.
More preferably A is phenyl, naphthyl, thiadiazolyl, thienyl, pyridyl or pyrimidyl.
Most preferably A is phenyl or thienyl.
In particular A is phenyl.
Preferably B is pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl, thiadiazolyl, imidazolyl, pyrazinyl, pyrimidyl, or oxazolyl.
More preferably B is pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl or oxazolyl.
Yet more preferably B is pyridyl, phenyl, thienyl, pyridazinyl or thiazolyl.
Yet more preferably B is phenyl, pyridyl or pyridazinyl.
Most preferably B is pyridyl.
Preferably X is pyridyl, thienyl, thiazolyl, furyl or phenyl.
Most preferably X is phenyl.
Preferably R is selected from the group consisting of CO2H and CO2R, e.g. CO2H.
Preferably R2 is selected from the group consisting of H and C1-6 alkyl, e.g. C1-6 alkyl.
Preferably R3 is H.
Preferably R4 is H.